This stratagem intends to improve the joining of PRA with the skin, improving its retention and anti-inflammatory effect. Gels were evaluated for various parameters such as pH, morphology, rheology, and swelling. In vitro drug release research and ex vivo permeation through the skin were carried out on Franz diffusion cells. Additionally, in vivo assays were carried out to evaluate the anti-inflammatory effect, and tolerance studies were performed in humans by evaluating the biomechanical properties. Results showed a rheological profile common of semi-solid pharmaceutical forms for dermal application, with sustained release up to 24 h. In vivo studies using PRA-NLC-Car and PRA-NLC-Sep in Mus musculus mice and hairless rats histologically demonstrated their efficacy in an inflammatory animal model study. No signs of skin irritation or modifications of the skin’s biophysical properties were identified and the gels were well tolerated. The results obtained from this investigation concluded that the developed semi-solid formulations represent a fitting drug delivery carrier for PRA’s transdermal delivery, enhancing its dermal retention and suggesting that they can be utilized as an interesting and effective topical treatment for local skin inflammation caused by a possible abrasion.Pranoprofen (PRA)-loaded nanostructured lipid carriers (NLC) have been dispersed into blank gels composed of 1% of Carbomer 940 (PRA-NLC-Car) and 3% of Sepigel The concept of abrasion means wearing down surfaces by friction. It is synonymous with erosion, wear, or chafing. In medicine, the term refers to the superficial ex-ulceration of the skin or mucous membranes by rubbing or scraping; that is, the procedure of mechanically removing different integument layers for cosmetic and/or therapeutic purposes ,2,3,4,5.The inflammatory process is a nonspecific immune response against external changes or cellular injury by harmful agents. This essential defense mechanism attempts to restore homeostasis to protect the injured tissues. Acute inflammation is the main and first response to exogenous factors caused by the collection of leukocytes that migrate from the blood to the injured areas ,7. When The primary mechanism of action of NSAIDs is the inhibition of cyclooxygenase (COX). Cyclooxygenase is required to convert arachidonic acid to thromboxane, prostaglandins, and prostacyclins . The theAs a potent non-steroidal anti-inflammatory drug (NSAID) we have pranoprofen (PRA), chemically known as 2- propanoic acid, that was authorized for the first time in China by the China food and drug administration (CFDA) in 1999 and is used as an alternative treatment for inflammation in ophthalmic therapy , and as an alternative treatment for osteoarthritis and rheumatoid arthritis ,11,12. PSkin treatments remain challenging due to the difficulty of controlling the fate of active ingredients (drug substances) in the skin ,16. Over® 940, is a cross-linked acrylic acid anionic polymer which increases viscosity, stabilizes emulsions, forms gels and suspends particles in hydrous formulations, is non-toxic, and exhibits minimal or no irritation potential at the concentrations applied in personal care and cosmetics products [Carbomer 940, also known as carbopolproducts . It is iproducts . Its gel® 305, also known as Farcosgel, is a product presented as a gelatinous, fluid, yellowish, opalescent dispersion used in gels and gel creams. It consists of polyacrylamide as a gelling agent, polyoxyethylene-7-lauryl ether as a non-ionic emulsifier, and isoparaffin as a fatty oil, which acts as a viscosifier and stabilizer for formulations. It comes in a ready-to-use liquid, pre-neutralized, and is effective over a wide pH range (pH 6.5 at 2%). It is an excellent stabilizer and texturizing agent [Sepigelng agent ,21. The ng agent .® 305 polymers were selected to bear PRA-loaded NLC. Besides the faster drug release and the higher extensibility, the Carbopol-based gel showed a greater amount of PRA retained in the skin after the permeation studies with the predicted plasma concentration at a steady state below the therapeutic range. Thus, it can be assumed that no systemic levels would be achieved and in turn unwanted side effects would be avoided. This study confirms that these formulations developed are a dermal delivery strategy and a safe alternative for modulating PRA release and promoting drug retention in the skin to manage inflammatory skin symptoms locally.In previous works, we reported the development of nanostructured lipid carriers loading PRA ,24. We f3 central composite factorial design as described elsewhere [® 80, and the concentration of solid lipids and liquid lipids, on the physicochemical properties were studied. The formulation with the best physicochemical characteristics and highest level of encapsulation efficiency (EE) was selected for further studies. To be concise, the developed PRA-NLC formulation shows a mean particle size of around 248.40 nm and polydispersity index values lower than 0.25, which are characteristic of monomodal systems, and a negative charge with a Zeta potential value of −10.70 mV. The percentage of EE was found to be around 99.7% [In order to obtain the desired PRA-NLC suspension, a design-of-experiment (DoE) approach was applied previously using a 2lsewhere . The eff® 305). The selected concentrations for our studies were 1% of Carbomer 940 (PRA-NLC-Car) and 3% of Sepigel® 305 (PRA-NLC-Sep) after examining different parameters such as color, homogeneity, consistency, and phase separation.The PRA-NLC-Car gel and the PRA-NLC-Sep gel exhibited a suitable incorporation of the PRA-NLC, showing white color, smooth consistency, good homogeneous appearance, and no phase separation. These parameters were analyzed after 24 h, 72 h, 7 days, 14 days, and 30 days and no changes were detected .The pH of a dermal formulation is considered an essential factor for its stability and compatibility with the skin, evading dermal irritation and protecting the skin from bacterial infections . The skiSeries car 4, car 25, and car 40 represent PRA-NLC-Car at 4 °C, 25 °C, and 40 °C, whilst Series sep4, sep25, and sep40 represent PRA-NLC-Sep at 4 °C, 25 °C, and 40 °C. The x-axis represents lagged time points for the given time lapses: fresh, 24 h, 72 h, 7 days, 14 days, and 30 days.−1. C=C stretching of its aromatic rings is presented at 1500 cm−1. Other peaks from C=O bonds (between 1650 and 1850 cm−1) can also be observed and there are several vibrations observed at the fingerprint region (600–1450 cm−1). FT-IR analysis suggests that there is no evidence of new covalent bonds between the drug (PRA) and Precirol® ATO5 and the polymers (Carbomer or Sepigel).Fourier-transform infrared spectroscopy (FT-IR) is an effective tool to confirm the analysis of bonds between molecules . Figure 2 = 0.999), and Ostwald-de-Waele and Cross best fit the PRA-NLC-Sep data (r2 = 0.999), which was expected in these types of semisolid formulations and usually clarified the pseudoplastic bearing over a wide range of shear rates. −1, the mean viscosity values obtained 2 days after the production at 25 °C were 9.854 × 102 ± 0.10 mPa·s for PRA-NLC-Car and 10.24 × 102 ± 0.16 mPa·s for PRA-NLC-Sep, proving repeatability between samples (n = 3) in the rheological data. For characterizing the flow properties of gels’ forms and forecasting their behavior during manufacturing, packaging, or final use, rheological studies are a valuable tool . The Her2, and a release constant (K) of 0.126 ± 0.015 g−1. PRA-NLC-Sep followed a hyperbola one-site model  = 32.010 ± 0.579 cm2. The spreadability results of this study indicate that both gels were easily spreadable with the exertion of a small amount of shear [The spreadability property is important because it indicates how the topical forms will behave when extruded from the container  and the application and uniformity of the dose, as a result having an impact on the therapeutic efficacy. Based on the mathematical modeling, PRA-NLC-Car followed a first-order  kinetic profile A, the exte model B, with aof shear ,29. −1 and K = 0.97 min−1, respectively. PRA-NLC-Car achieved almost 100% swelling after 40 min and PRA-NLC-Sep after 20 min.Swelling studies were performed to assess the capacity of the gels to absorb solvent PBS (pH 5.5) within their structure . Dehydra−1 for PRA-NLC-Car and 0.055 min−1 for PRA-NLC-Sep.Degradation experiments were carried out by immersing fresh samples of gels in PBS (pH 5.5) and evaluating the weight changes at specified time intervals. The percentage porosity was 84.64% ± 0.17% for PRA-NLC-Car and 76.21% ± 0.16% for PRA-NLC-Sep. It is known that gels with small pore sizes are characterized as having a forceful viscous coupling within the formed network and the solvent, inhibiting the polymer network’s movement relative to the solvent ,32. ThesFor both gels, the release profile of PRA follows a nonlinear regression. PRA-NLC-Car and PRA-NLC-Sep were tested ex vivo in human abdominal skin for up to 28 h. ssJ (flow) and Kp (permeability coefficient) were calculated from the accumulative permeated amount of PRA (µg) as a function of time. PRA-NLC-Sep showed higher ssJ and Kp. However, the amount of PRA retained in the skin (Qret) is greater with PRA-NLC-Car than PRA-NLC-Sep. Predicted steady-state plasma concentration (Css) values obtained for PRA-NLC-Car and PRA-NLC-Sep, taking into account a hypothetical zone of application of 100 cm2, were lower than the stated therapeutic plasma concentration corresponding to 4.89 ± 1.29 µg/mL for old-age and 10.19 ± 2.43 µg/mL for young humans [The values of the parameters g humans . As a reA mouse ear inflammation model induced by topical application of xylol was used to assess the anti-inflammatory activity of PRA-NLC-Car and PRA-NLC-Sep. Mice’s ears were exposed to xylol to induce inflammation of the tissue. As can be observed in Additionally, hairless rat back skins were exposed to microneedle abrasion, and the skin histology in control conditions shows the scar after the procedure A. In FigssJ and Kp. However, the PRA-NLC-Car showed higher values of Qret on the skin. Taking into consideration the in vivo study, both formulations showed excellent anti-inflammatory activity, with a reduction in leukocytic infiltrate after the topical treatment. These results suggest that either one or the other formulation could be used, depending on the inflammatory skin disease, with excellent results. This article brings to light two new topical formulations containing encapsulated PRA, which could be used for a variety of skin inflammatory processes such as abrasion caused by depilation.The present work demonstrates that the two gels developed (PRA-NLC-Car and PRA-NLC-Sep) were well characterized physiochemically, with good stability at different temperatures and well tolerated for dermal application. Moreover, the skin barrier function was preserved, and no visible irritation was identified. Additionally, PRA- NLC-Sep could release the drug faster than PRA-NLC-Car, which showed higher values for Ricinus communis L.) and Tween® 80 (CAS 9005-65-6) (Polyoxyethylene 20 sorbitan monooleate) were obtained from Sigma-Aldrich Química . Precirol® ATO 5 (CAS 8067-32-1)  and LAS (CAS 61791-29-5) (PEG-8 Caprylic/Capric Glycerides) were obtained from Gattefosse . Carbomer 940 (CAS 9003-01-4) (acrylic acid polymer) was purchased from Fagron ibérica . Sepigel 305® (CAS 64742-47-8)  was purchased from Acofarma . The purified water utilized in all experiments was collected from a MilliQ® Plus System , lab-supplied. The tablets of phosphate-buffered saline (PBS) were acquired from Sigma-Aldrich Chemie  as well as processed as specified by the manufacturer and stored in fridge for further use. All other chemicals for analytical experiments and reagents utilized in the research were of analytical or high-performance liquid chromatography (HPLC) grade and acquired from Fisher Scientific .Pranoprofen (CAS 52549-17-4) was acquired from Alcon Cusi . Castor oil (CAS 8001-79-4)  as liquid lipids, and 1.5 wt% of PRA, was melted in a water bath at 85 °C to obtain a clear homogeneous lipid phase solution. This lipid phase was added to an aqueous phase solution containing Tween® 80 that was heated simultaneously at the same temperature. A dispersion (premix) was formed using an ultra turrax  for 45 s at 8000 rpm. The dispersion was passed thrice through a high-pressure homogenizer  at 85 °C and 800 bar. The obtained nanoemulsion was cooled down to 25 °C (room temperature) to recrystallize the lipid and form the PRA-NLC. The PRA-NLC formulation was optimized by a factorial design 23, described previously [PRA-NLC was prepared by a high-pressure homogenization technique ,33, optieviously . Previoueviously .-w/v), dispersed in milli Q water, and permitted to hydrate for a day. Afterward, it was stirred moderately and then the pH was adjusted with triethanolamine to ensure a eudermic pH. The PRA-NLC suspension previously optimized and selected was incorporated into the blank gel under continuous magnetic stirring . It was left without stirring until it reached equilibrium for a day at 25 °C (room temperature) prior to use.PRA-NLC-Car: The blank gel was developed with carbomer 940 (1% -® (3% w/v) dispersed in milli Q water under continuous stirring to obtain the gel formulation. The PRA-NLC was added to the gel under magnetic stirring until complete homogenization with a final formula composition of 10.7 mg PRA/g gel to maintain an effective active ingredient concentration. The gel was left without stirring right up until achieved equilibrium for a day at 25 °C (room temperature) prior to use. PRA-NLC-Sep: The blank gel was prepared with Sepigel 305Values of pH of PRA-NLC-Car and PRA-NLC-Sep gels were measured by a calibrated digital pH-metre micro . It is useful to check gels’ compatibility and the adequacy for use on damaged skin and as a mechanism to support the stability of the gels .Small samples of PRA-NLC-Car and PRA-NLC-Sep were dried over 9 days in a vacuum desiccator to examine their morphology. When completely dried, a small quantity was coated using a slim carbon layer as a conductive agent  with an −1.To obtain FT-IR spectra of dried PRA-NLC-Car, PRA-NLC-Sep, and PRA, a Thermo Scientific Nicolet iZ10 with an ATR diamond and DTGS detector were used. The scanning range was 525–4000 cm® Job Manager v. 4.0  for testing and HaakeRheowin® Data Manager v.4.0  for analysis of the acquired data. Viscosity and flow curves were measured at 25 °C. The conditions of the shear rate ramp program adjusted a 3 min ramp-up period from 0 to 50 s−1, a 1 min uniform-shear-rate period from 50 s−1, and a ramp down from 50 to 0 s−1 for 3 min. The rotational flow curve values were fitted to various mathematical model equations: Newton, Ostwald-de-Waele, Bingham, Casson, Cross, and Herschel–Bulkley [−1 for each formulation.Forty-eight hours after preparation of the gels, rheological measurements were determined in triplicate with a rotational rheometer  provided with a cone–plate setup (the gap between cone and plate was 0.106 mm), with a plate and a movable higher cone Haake C60/2° Ti . The rheometer was equipped with a Thermo Haake Phoenix II + Haake C25P temperature controller device  and operated by a HaakeRheowin–Bulkley . The besS is the spreading area or extensibility (cm2) computed from the utilized mass of sample (g), and d is the average diameter (cm) impacted by the sample. Experimental results were analyzed according to the best kinetic model and fitted to different mathematical models with the statistical program GraphPad Prism® v.8.0.0, GraphPad Software, San Diego, CA, USA. The r value confirmed the model fitting.Extensibility was determined by placing samples of 0.5 g of each gel (PRA-NLC-Car and PRA-NLC-Sep) between a two-platform device  (the glaSR) and the degradation experiment (which was expressed as the percentage of weight loss (WL)) were evaluated based on a gravimetric method. Samples of dried gel were used to carry out the swelling test, and samples of fresh gel were used for the degradation test. In both trials, the samples were immersed in PBS (pH = 5.5) at a temperature of 32 °C for 30 min and were withdrawn and weighed, subsequently blotting the surface water at predetermined intervals. The SR ratio was calculated based on Equation (2) and represented by a kinetic model:Ws denotes the mass (weight) of the swollen PRA-NLC-Car and PRA-NLC-Sep samples at specified times, and Wd is the mass (weight) of dried gels.The parameters of swelling ratio (WL) with the following equation and represented by a kinetic model:Wi is the initial mass (weight) of the samples of PRA-NLC-Car and PRA-NLC-Sep after each immersion after specified interval times and Wd is the mass (weight) of the gel at various time points.The degradation rate of the gel was determined as the percentage of weight loss (P) of the gels was calculated using the following expression:W2 denotes the mass (weight) of the samples after each immersion in ethanol every 2 min, W1 is the mass (weight) of the dried samples, ð = density of the ethanol, and V = volume of the sample used.The porosity percentage was assayed based on the sinking of the PRA-NLC-Car and PRA-NLC-Sep samples after drying in absolute ethanol for 20 min and weighing them every 2 min when the excess was blotted. The porosity (v/v) for a day, after previously being mounted in the Franz cell between the donor and receptor compartment. The receptor used was phosphate-buffered saline (PBS) (pH 7.4) kept with continuous stirring at 700 rpm for assuring sink conditions. A summary of the experimental conditions is given in In vitro release assays were conducted with amber vertical glass Franz diffusion cells ,38 (400 2) [The amount of PRA released was adjusted to different kinetic models; the best model-fitting aptness was selected by calculating the value of the coefficient of determination (r2) .Ex vivo human skin permeation was performed using the same Franz diffusion cells as in in vitro release studies ,38. The 2, and PBS (pH 7.4) was utilized to fill the receptor chamber. The samples of the gels were added to the donor chamber directly in contact with the skin and covered with parafilm® to prevent evaporation. An amount of 200 µL of samples was withdrawn from the receptor chamber at predetermined time points and replaced by an equal amount of the receptor medium. The skin diffusion area was 0.64 cmv/v) and sonicated in an ultrasound bath for 25 min to extract the total retained quantity of PRA from the pieces of skin (Qret). The quantity of PRA retained and permeated was determined by HPLC [Once the experiment was complete, the skin was removed from the cells and rinsed with 0.05% sodium lauryl sulfate and purified water to eliminate the gel on the skin’s surface. The permeation area of the skin in direct contact with the formulation was cut out, weighed, and immersed in methanol/water  and the transdermal permeability coefficient  were calculated according to the following equations [Qt (μg) is the quantity (amount) of drug permeated across the skin and thus detected in the receptor chamber, A (cm2) denotes the active cross-sectional area (accessible for diffusion), t (h) is the time of exposure, and C0 is the primary drug concentration in the donor chamber.The steady-state flux across the skin (quations :(5)Jss=QssC of the drug that would penetrate the skin post topical administration was estimated with the following equation:ssJ is the flux, A is the hypothetical area of application (considering in this case 100 cm2), and pCL is the human plasma clearance of PRA  [In view of the pharmacokinetic parameters of the PRA for young and old-age humans, the estimated steady-state plasma theoretical concentration ctively) ,42.The in vivo studies were performed based on the Academic Ethics Committee of the Nursery of the Autonomous University of the State of Morelos (Mexico) that approved the Study Protocol on 19 January 2023, and the Official Mexican Standard for the Care and Management of Animals (code: NOM-062-ZOO-1999).Mus musculus mice  (n = 9) were used for the mouse ear inflammation model. The animals were permanently maintained under a controlled temperature and photoperiod (light between 06:00 and 18:00 h). Food and water were available ad libitum.Male n = 3), and a third group received the PRA-NLC-Sep treatment (n = 3). In addition, a fourth group of untreated, healthy mice was used as a negative control (n = 3). The treatment was applied twice for one day. Finally, mice were sacrificed by cervical dislocation, and the right ears were excised for histological studies. Female hairless rats  (n = 9) were used in the rat skin model for the abrasion test. The animals were permanently maintained under a controlled temperature and photoperiod (light between 6:00 a.m. and 6:00 p.m.). Food and water were available ad libitum.The inflammatory process was induced topically by applying xylol to the right ear for 40 min . Three in = 3). A second group was damaged and given treatment with PRA-NLC-Car gel (n = 3), and the other group was damaged and provided treatment with PRA-NLC-Sep (n = 3). The treatment was applicated twice for one day. Finally, rats were sacrificed and the backs were cut for histological studies.The damage was induced topically on the back and by applying abrasion with a special glove. Three damaged rats were used as a group for control  was used, and for measurement of the thickness a digital thickness gauge of 0 to 10 mm  was used.After applying the formulations, mice and rats were sacrificed. The mice’s ears were obtained, and the skin of the rats’ backs was surgically excised to study the anti-inflammatory effect of the formulations. The tissues were soaked in 4% buffered formaldehyde for 24 h, dehydrated in a gradient of ethanol, and finally embedded in melted paraffin. Blocks were cut into 5 mm pieces, stained with hematoxylin and eosin, and viewed under a microscope (Olympus BX41 and Olympus XC50 camera).In vivo skin human tolerance studies by evaluating biomechanical properties were authorized by the University of Barcelona Ethics Committee on 30 January 2019 (IRB00003099).® , which measures the amount of water entering the environment (atmosphere) around the epidermal layer of the skin through diffusion and evaporation processes [2·h) were expressed as mean ± SD (n = 10).Total skin water loss (TEWL) was evaluated with a Tewameterrocesses ,43. Ten ®  and was determined before application in the basal state and 5, 15 min, 1 h and 2 h post application of PRA-NLC-Car and PRA-NLC-Sep gels on the treated area. The measurements were carried out using the capacitance method, which takes advantage of water’s relatively high dielectric constant compared to other skin substances. SCH data (arbitrary units) are expressed as the mean ± SD (n = 10).The evaluation of the hydration of the stratum corneum (SCH) was carried out with an 825 Corneometer


As a promising support material, red phosphorus (RP) based SACs are still rarely investigated. In this work, we have carried out systematic theoretical investigations by anchoring TM atoms  on RP for efficient photocatalytic H2 generation. Our density functional theory (DFT) calculations have revealed that 3d orbitals of TM locate close to the Fermi level to guarantee efficient electron transfer for photocatalytic performances. Compared with pristine RP, the introduction of single atom TM on the surface exhibit narrowed bandgaps, resulting in easier spatial separation for photon-generated charge carriers and an extended photocatalytic absorption window to the NIR range. Meanwhile, the H2O adsorptions are also highly preferred on the TM single atoms with strong electron exchange, which benefits the subsequent water-dissociation process. Due to the optimized electronic structure, the activation energy barrier of water-splitting has been remarkably reduced in RP-based SACs, revealing their promising potential for high-efficiency H2 production. Our comprehensive explorations and screening of novel RP-based SACs will offer a good reference for further designing novel photocatalysts for high-efficiency H2 generation.Transition metal (TM) single atom catalysts (SACs) are of great potential for photocatalytic H Besides, the kinetics for water adsorption and activation, the energy barrier for H adsorption, and the activation barrier of H2 evolution are demonstrated in detail. This work will offer an atomic scale insight into the reaction mechanisms of TMs-RP SACs based photocatalytic H2 evolution. Meanwhile, the detailed theoretical explorations also serve as fundamental theoretical references for the rational design of TMs-based SACs with enhanced photocatalytic performances in the future.In this work, we have conducted comprehensive calculations of the electronic structures of commonly used TMs-based SACs  on RP support (denote as TMs-RP) to predict their performances of photocatalytic H−7 eV/atom; the Max. Hellmann-Feynman force per atom is 0.01 eV/Å; the Max. stress is 0.02 GPa; and the Max. displacement is 5.0 × 10−4 Å. According to previous experimental studies, the [001]-oriented Hittorf’s phosphorus has been proven to be very efficient for water-splitting.  serves as a key descriptor for the prediction of HER activity, which can be calculated based on the following equation  calculations within the CASTEP module. . The geolitting. . Thus, ilitting. , with a litting. . The topequation :ΔEH=EH*2/H2O and CBM higher than the reduction level of H2/H+. Thus, the bandgap values and band positions of photocatalysts can largely reflect their absorption window toward sunlight, and the relative positions of VBM and CBM with reference to standard hydrogen electrode potential can be used to predict the redox tendency for water splitting.For photocatalytic reactions, the excitation energy required for electron-hole separation is largely decided by the bandgap value of the semiconductor photocatalyst. To make the most use of solar energy, the bandgap of the photocatalysts is expected to be located within the spectrum of sunlight, namely, from the UV to NIR range. In fact, most of the solar energy (nearly 95%) is constituted by visible light (43%) and NIR (52%). To match the Vis-NIR excitation window of sunlight, the bandgap of the candidate photocatalyst is expected to be less than 3.10 eV. And based on the redox potential of water, to drive the water splitting reaction, the bandgap value is projected to be wider than 1.23 eV with the location of VBM lower than the oxidation level of OTo evaluate the bandgap matching degree of the TMs-RP, we have first compared the band structure of pristine RP  with Fe-F) and VBM  is another important indicator of electronic structures. In  and VBM . Especiam the EF . This reF and vacuum level.  are located above O2/H2O level, theoretically indicating the weak capability for oxygen evolution. Previous works have revealed the slight mismatching of bandgaps and work functions between theoretical calculations and experimental data. (In the acidic condition (pH = 0 in aqueous solution), the CBM of pristine RP and TM-anchored RP are all located above the reduction level of Htendency . Howeveral data. . By cons2O are sensitive to pH variation, the photocatalytic driving force for HER and OER can be well tuned by the pH manipulation based on the following Nernst equations:  does not follow the Nernstian dependence on pH (−0.059 eV/pH).  adsorbed on the catalytic surface in HER. The corresponding band positions are stationary with redox potentials of H2O in different pH values to reveal the reaction tendency for HER and OER. (2/H+ level and O2/H2O level move up to a more negative position (with reference to SHE) at −0.41 eV and 0.82 eV, respectively . . The sloand OER. . In the ectively . Accordiectively . Thus, wBesides thermodynamic driving force, many other factors such as microstructures at the micro or nanoscale, adsorption energy, surface/interface morphological properties, and coupling effects with cocatalyst components also have significant influence on photocatalytic performance. . For a b2O adsorption energy has a great influence on interfacial charge transfer, and decides the aggregation extent of H2O molecules near the catalytic active sites, which further triggers the concentration effect and results in more H* generated from water splitting. . Then, the electrons aggregate between TM and H2O with the formation of an obvious adsorption bond. According to the calculated H2O adsorption energy values in 2O adsorption processes in pristine-RP and TMs-RP are all exothermic, indicating spontaneous adsorption trends. By the loading of TMs SA atoms on the RP surface, the water adsorption capacity has been improved remarkably. Among the four TM-based SACs, Fe-RP (−0.61 eV), Co-RP (−0.67 eV), and Ni-RP (−0.60 eV) exhibit better H2O affinity than Cu-RP (−0.45 eV). If the H2O adsorption is too strong, the over-adsorption induces poison effects on the catalytic surface. , 0.89 eV , and 1.27 eV  respectively, but their calculated ΔEH values are still much less than that of pristine-RP. To sum up, under an acidic environment, the H* is mainly from H+ in the solution, where the adsorption energy of H* on the catalyst surface is the main influence factor for HER. Based on the calculated ΔEH, in both situations, H adsorbed on TM atoms (Fe-RP < Co-RP < Cu-RP < Ni-RP < RP) or on coordinated P atoms (Fe-RP < Co-RP < H-P1-Cu < Ni-RP = H-P2-Cu < H-P3-Cu < RP), SA TMs-RP have much lower energy barriers than pristine-RP for HER. It is worth noting that in the acidic condition, Fe-RP exhibits the lowest energy HER barrier in both H-adsorption sites discussed above.Besides the water adsorption comparisons, H adsorption is another determinant factor in HER, where both too negative and too positive values are not beneficial for the HER. Based on the adsorption sites, the calculations for H-adsorption reaction energy change are classified into two different types . One con2O molecules and the desorption of OH− are important influence factors in reaction energy changes. As shown in 2 generation is compared. For all the catalysts, the water dissociation step requires the largest energy costs as the rate-determining step. We have considered two different situations for water dissociation to compare the reaction energy barriers. For the adsorption of OH and H on TM atoms and neighboring P atoms, respectively, the Co-RP and Ni-RP show an energy barrier of 0.90 eV and 1.20 eV, respectively. Different from other TMs-RP types, the anchored single-atom Cu is not symmetrically located in the hexatomic ring of supporting P atoms, which leads to three possible P sites for water dissociations with a water dissociation energy of 1.50 eV, 1.10 eV, and 1.75 eV, respectively  or even becomes spontaneous. In comparison, the pristine RP exhibits a much higher energy cost for the OH− desorption, which leads to the poisoning effect of active sites and lowers the overall photocatalysis performances. Moreover, only Cu-RP and Co-RP (H adsorbed on Co atoms) show endothermic trends for the direct H2 formation step while other TMs-RP all show the exothermic trend.For the photocatalytic mechanism in neutral and alkaline environments, H* is mainly from water dissociation. The energy barrier for the dissociation of Hectively . For wat2O* molecules, the water adsorption energy and dissociation energy are the two main influencing factors for HER. The water adsorption energy follows the order of Co-RP < Fe-RP < Ni-RP < Cu-RP < RP, while the water dissociation energy, which is the largest energy barrier, follows the order of Fe-RP < RP < Co-RP < Cu-RP < Ni-RP. Less H2O molecules tend to be gathered around the active catalytic sites on pristine RP surface because its adsorption energy is only −0.04 eV. Thus, although pristine-RP has a relatively small energy barrier for water dissociation, its HER activity will be limited due to the inadequate gathering of reactant H2O molecules on the catalytic surface. The adsorption energies of water molecules on Fe-RP, Co-RP, and Ni-RP are much lower than that of pristine-RP and Cu-RP, leading to more efficient accumulation of H2O molecules on these three catalyst surfaces, which will benefit the following water dissociation process. Further taking the order of water dissociation energy into consideration, the activation barriers of Ni-RP and Cu-RP are relatively larger. Overall, in neutral and alkaline conditions, the Fe-RP and Co-RP can potentially offer superior HER performance.For TMs-RP, the energy barriers for OH* desorption are relatively small. In neutral and alkaline environments, since the H* is mainly from the dissociation products (H* and OH*) of adsorbed H2 generation.Combining the band alignment and reaction energy, we have proposed photocatalyst candidates for different environments. For the acidic solution, Fe-RP, Co-RP, and Cu-RP are the most promising candidates. For the neutral environments, Fe-RP delivers better performances than other TMs-RP, indicating novel selections to achieve even superior performances than the reported Ni-RP catalysts. . In a we2 generation. For the neutral and alkaline solution, all TMs-RP catalysts exhibit much stronger H2O adsorption than pristine RP, which promotes the following dissociation to supply sufficient proton. In particular, Fe-RP and Co-RP has shown the lowest energy barriers for H2 generation. Overall, we notice that there is no TMs-RP that has superiority in all pH environments, where different TMs have their specific merits. Based on the comprehensive investigations of different parameters, we think that the TMs-RP possesses great potential and flexibility to achieve efficient H2 generation in different environments. This work has supplied important theoretical references and opened great opportunities for experimental researchers to further optimize the photocatalytic activity in advanced and novel SACs.In this work, we have conducted comprehensive investigations on photocatalytic activity regarding the electronic properties, adsorption properties, and reaction energy change for four kinds of SACs by anchoring TM  single atoms on RP. With the introduction of the single-atom TM anchored on the surface, the sunlight absorption window is extended from red light to a higher NIR region, which potentially improves the utilization rate of solar energy. The electronic structures indicate that Co-RP and Ni-RP show highly catalytic active 3d orbitals to benefit the electron transfer during photocatalysis. Considering the band alignments of photocatalysts, Ni-RP indicates its superiority in supporting HER capability over a wide pH range. Under the acidic environment, Cu-RP, Fe-RP, and Co-RP demonstrate the most preferred proton binding to promote H


Background: Dark-field imaging is a novel imaging modality that allows for the assessment of material interfaces by exploiting the wave character of x-ray. While it has been extensively studied in chest imaging, only little is known about the modality for imaging other tissues. Therefore, the purpose of this study was to evaluate whether a clinical X-ray dark-field scanner prototype allows for the assessment of osteoporosis.Materials and methods: In this prospective study we examined human cadaveric lumbar spine specimens . We used a clinical prototype for dark-field radiography that yields both attenuation and dark-field images. All specimens were scanned in lateral orientation in vertical and horizontal position. All specimens were additionally imaged with CT as reference. Bone mineral density (BMD) values were derived from asynchronously calibrated quantitative CT measurements. Correlations between attenuation signal, dark-field signal and BMD were assessed using Spearman’s rank correlation coefficients. The capability of the dark-field signal for the detection of osteoporosis/osteopenia was evaluated with receiver operating characteristics (ROC) curve analysis.Results: A total of 58 vertebrae from 20 human cadaveric spine specimens  were studied. The dark-field signal was positively correlated with the BMD, both in vertical  and horizontal position . Also, the dark-field signal ratio was positively correlated with BMD . No correlation was found between the signal ratio of attenuation signal and BMD . For the differentiation between specimens with and without osteoporosis/osteopenia, the area under the ROC curve (AUC) was 0.80 for the dark-field signal in vertical position.Conclusion: Dark-field imaging allows for the differentiation between spine specimens with and without osteoporosis/osteopenia and may therefore be a potential biomarker for bone stability. Osteoporosis is a metabolic bone disease leading to reduced bone strength and consequently to fragility fractures . OsteopoGrating-based X-ray dark-field imaging  measuresBased on findings in previous studies with smaller specimens , we hypoTherefore, the purpose of this study was to evaluate whether a clinical X-ray dark-field prototype enables the assessment of osteoporosis in lumbar spine specimens.Institutional review board approval was obtained prior to this study . This study was conducted in accordance with the Declaration of Helsinki. Lumbar spine specimens were harvested  from human cadavers within 24 h after death. Inclusion criteria was a clinically indicated post-mortem examination. Exclusion criteria were previous spine surgery and known osseous metastatic disease. For one specimen, only L2 and L3 were harvested, resulting in a total of 59 vertebrae from 20 human cadaveric spine specimens.3 were considered as osteoporotic/osteopenic, BMD values ≥120 mg/cm3 were considered normal  with the following parameters: Collimation, 0.6 mm; pixel spacing, 0.3 mm; spiral pitch factor, 0.39; tube voltage (peak), 120 kV; tube current, 347 mA. BMD values were derived from asynchronously calibrated quantitative CT examinations . Hounsfid normal .4, Trixell, Moirans, France) in combination with a Talbot-Lau interferometer with three gratings. From each acquisition, both attenuation and dark-field image can be reconstructed. To increase the setup’s sensitivity for assessment of osseous structure, we chose a larger distance between sample and analyzer grating than for patients in previous studies . It consists of conventional medical X-ray devices  were tested using Wilcoxon Mann-Whitney U test. The utility of the dark-field signal for prediction of osteoporosis/osteopenia was assessed using receiver-operating-characteristic (ROC) curves and the respective area under the curve (AUC). A significance level of .05 was used for all tests.Statistical analysis was performed using Python, specifically NumPy  and SciPWe studied 58 vertebrae from spine specimens from 20 donors . The average age of the donors was 73 years ±13 [standard deviation], the average weight was 87 kg ± 29, and the average height was 165 cm ± 8 .3. It was 75 ± 19 mg/cm3 in the osteoporotic/osteopenic subgroup (n = 23) and 184 ± 28 mg/cm3 in the group without osteoporosis/osteopenia (n = 35). For 11 specimens all vertebrae were osteoporotic/osteopenic (33 vertebrae) and for 7 specimens all vertebrae were non-osteoporotic/osteopenic . In two specimens two vertebrae were osteoporotic/osteopenic and one was non-osteoporotic/osteopenic each. The average mean dark-field signal across all vertebrae increased from 0.27 ± 0.06 in vertical position to 0.32 ± 0.06 in horizontal position (p < .001), the average mean attenuation signal was 0.27 ± 0.09 in both vertical position and horizontal position (p = .98).p < .001) and horizontal position . When calculating signal ratios between vertical and horizontal position, the average ratio was 1.00 ± 0.07 for the attenuation signal and 0.84 ± 0.07 for the dark-field signal. No correlation was found between the signal ratio of attenuation signal and BMD . The dark-field signal ratio, however, was positively correlated with BMD .The attenuation signal was positively correlated with the BMD, both in vertical . The average dark-field signal was also significantly lower in vertebrae with osteoporosis/osteopenia for both vertical  and horizontal orientation . For the differentiation between vertebrae with and without osteoporosis/osteopenia, the area under the receiver operating characteristic curve (AUC) was 0.88 for attenuation signal in vertical position, 0.86 for attenuation signal in horizontal position, 0.80 for dark-field signal in vertical position, 0.76 for dark-field signal in horizontal position, and 0.65 for ratio of dark-field signal in vertical to horizontal position. The optimum cutoff value in dark-field signal in vertical scanning position was .24, the respective Youden index was J = 1.61. Applying this cutoff value for the differentiation between specimens with and without osteoporosis/osteopenia, sensitivity, specificity, and accuracy were 0.61, 1.00, and 0.83, respectively.p = 0.02), while the ratio for attenuation signal showed no correlation with BMD . For the differentiation between specimens with and without osteoporosis/osteopenia, the AUC was 0.80 for dark-field signal in vertical position with an optimum cutoff value of .24, yielding a sensitivity, specificity, and accuracy of 0.61, 1.00, and .84, respectively.In this prospective study, we evaluated whether a clinical prototype for dark-field radiography enables the assessment of osteoporosis in human cadaveric spine specimens. Both the attenuation signal and the dark-field signal were positively correlated with the BMD, both in vertical and in horizontal position. The ratio of dark-field signal in vertical and horizontal scanning position was also positively correlated with BMD (r = 0.30, X-ray dark-field imaging is an imaging technique that has recently reached the human scale. It takes advantage of the wave properties of X-rays, as material interfaces generate small-angle scattering resulting in dark-field signal . PreviouAnother important finding results from the fact that our prototype scanner is sensitive to material interfaces only in horizontal position, that is in the orientation of the gratings of the Talbot-Lau-Interferometer. Thus, in order to evaluate whether dark-field signal indeed is generated by interfaces between trabecula and bone marrow, we scanned the specimens both in vertical and horizontal position. The results demonstrated that the dark-field signal was higher in the horizontal position compared to the vertical position, suggesting a higher number of trabeculae in vertical orientation compared to horizontal orientation, which is in line with previous findings . As expein-vivo patient setting, however, the attenuation of the vertebra would be superimposed with the attenuation of surrounding tissue, which is the reason that conventional attenuation cannot be used for BMD determination. Currently in clinical routine DXA, a dual-energy technique, is used as reference standard for the BMD assessment. DXA measurements are mainly acquired in an anterior-posterior projection due to the lower effective dose compared to a lateral acquisition. Nevertheless, previous studies have shown DXA measurements to be insufficient for BMD determination due to, e.g., superimposition of degenerated posterior elements of the vertebrae (in vivo studies are needed for further investigation.When calculating the AUC for the differentiation between specimens with and without osteoporosis/osteopenia, the AUC values for attenuation signal were higher compared to dark-field signal intensities. This was expected, since the attenuation signal is directly proportional to the specimen density, which can also be quantified with the BMD measurements in osteoporotic and non-osteoporotic vertebrae, which served as standard of reference in this study. Yet, in an ertebrae . Since dThis is the first study to evaluate dark-field imaging for the assessment of osteoporosis in a human sized scanner prototype. Our results are consistent with Eggl et al., who previously found a higher anisotropy in osteoporotic vertebrae, apposite to a changing trabecular structure in a much smaller number of osteoporotic specimens . Moreoveex-vivo experimental setting lacking surrounding tissue. Also, BMD measurement from CT have previously shown to be a more reliable method for the assessment of bone stability (ex-vivo with only little surrounding tissue, the results need to be further investigated in vivo studies in the future.This study has limitations. First, we did not correct for different sample thicknesses influencing the measured signals. Second, we used qCT measurements for the quantification of BMD and not DXA measurements, since robust DXA measurements were insufficient in the spine specimens. This was due to the tability . Third, In conclusion, a prototype dark-field x-ray imaging system indeed yields a measurable signal from trabeculae within human lumbar specimens, and allows the differentiation between vertebrae with and without osteoporosis/osteopenia. This suggests that the information on trabecular bone assessed using dark field x-ray imaging may complement the information obtained on bone mineral density and therefore may increase the diagnostic confidence in osteoporotic patients.


Antibody–drug conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs by a linker. They are designed to selectively bind target antigens and present a promising cancer treatment without the debilitating side effects of conventional chemotherapies. Ado-trastuzumab emtansine (T-DM1) is an ADC that received US FDA approval for the treatment of HER2-positive breast cancer. The purpose of this study was to optimize methods for the quantification of T-DM1 in rats. We optimized four analytical methods: (1) an enzyme-linked immunosorbent assay (ELISA) to quantify the total trastuzumab levels in all drug-to-antibody ratios (DARs), including DAR 0; (2) an ELISA to quantify the conjugated trastuzumab levels in all DARs except DAR 0; (3) an LC–MS/MS analysis to quantify the levels of released DM1; and (4) a bridging ELISA to quantify the level of anti-drug antibodies (ADAs) of T-DM1. We analyzed serum and plasma samples from rats injected intravenously with T-DM1  using these optimized methods. Based on these applied analytical methods, we evaluated the quantification, pharmacokinetics, and immunogenicity of T-DM1. This study establishes the systematic bioanalysis of ADCs with validated assays, including drug stability in matrix and ADA assay, for future investigation on the efficacy and safety of ADC development. The others, Adcetris®, Besponsa®, Lumoxiti®, Mylotarg®, Polivy®, Blenrep®, and Zynlonta®, were approved for hematologic malignancies + to [485.3]+. The MRM transition for maytansine was [692.2]+ to [547.2]+.DM1-NEM was quantified via an API 5000 mass spectrometer  coupled with an Agilent 1260 HPLC system . The column used was an Atlantis dC18 column . Chromatographic separation was conducted with a gradient elution at a flow rate of 500 µL/min as follows: the mobile phase consisted of 5 mM ammonium acetate in a 0.1% formic acid aqueous solution as A and 5 mM ammonium acetate in acetonitrile: HTo measure the ADA responses of T-DM1, a bridging ELISA method was used with biotinylated T-DM1 and streptavidin HRP. Thereafter, the TMB-induced colorimetric signal was stopped to measure the optical density at 450 nm using a SpectraMax M3 microplate reader (Molecular Devices Inc.). To assess immunogenicity, screening assays were performed by detecting ADA binding to T-DM1 in the samples. To determine whether the sample was positive or not, the negative cutoff value was determined using the following equation: mean absorbance of negative control sample × normalization factor. The samples determined to be positive were subjected to a confirmatory assay to verify whether the ADAs were specific to T-DM1. The samples were treated with 1 mg/mL T-DM1, and the measured values were observed in comparison with the corresponding untreated samples.® 1.5, and a 1/x2-weighted linear regression model was used for data processing. The concentration–time curve was plotted using WinNonlin version 8.1.0 . The PK parameters were calculated with noncompartmental analysis (NCA) models. All the graphs were generated using GraphPad Prism version 9.5.0 .The data from the ELISA methods were collected and analyzed using SoftMax Pro version 5.4.1 software (Molecular Devices Inc.), and a logistic model (4-parameter) was used for data processing and curve fitting. The data from the LC–MS/MS methods were analyzed using AnalystConsidering the properties of T-DM1, two ELISA methods were developed to compare the quantification of selective DM-1-conjugated trastuzumab to nonselective total trastuzumab. During validation, typical parameters were evaluated by both ELISA methods . The resTo determine the level of unconjugated DM1 in rat plasma, the LC–MS/MS assay was partially validated. The parameters evaluated during validation are described in We performed additional unique experiments for the evaluation of ADCs. As mentioned previously, the ELISA for the total trastuzumab was designed to detect conjugated and unconjugated T-DM1. To demonstrate the ability of the assay to quantify both the conjugated and unconjugated trastuzumab, T-DM1 (as a mixture of conjugated and unconjugated antibodies) and trastuzumab (as a completely unconjugated antibody) were added to the rat serum at different ratios and analyzed with T-DM1 calibration standards in the total trastuzumab ELISA . The %REmax upon the administration of T-DM1 into the rats, as Cmax was 848.03 μg/mL for T-DM1 and increased to 1032.72 μg/mL for the total trastuzumab, as well as suggesting the appearance of deconjugated DM1. Moreover, the results revealed that T-DM1 exhibited an approximately two-fold increase in half-life for the total trastuzumab compared to T-DM1 or DM1, which showed the bioavailability of T-DM1 after administration. The steady-state volume of distribution of T-DM1 was similar to that of total trastuzumab, but the T-DM1 clearance was approximately 1.9-fold times faster than that of the total trastuzumab. The unconjugated DM1 had a significantly larger volume of distribution at the steady state  and a faster clearance than both T-DM1 and the total trastuzumab. Our data demonstrated that the low levels of DM1-conjugated trastuzumab in rats had similar patterns to those of monkey and human PK profiles [The PK properties of T-DM1, total trastuzumab, and DM1 were evaluated. profiles .p > 0.05). The mean absorbance value of the naive blank sera was 0.067 , and the normalization factor was multiplied by 1.14 based on the assay validation experiments in rats. T-DM1 was treated with 24 individual rat blank sera to determine the signal inhibition at the basal level, and the specificity cutoff value was determined to be 22 , and the cutoff values used for the sample analysis were obtained from this ELISA method. The cutoff was determined as recommended by Mire-Sluis et al. , and 24 to be 22 B.Serum samples obtained from T-DM1-administered rats were tested using the bridging ELISA as previously described. As a result of evaluating positivity in the screening assay, 8 out of the 16 collected samples showed absorbance values greater than the negative cutoff value. Following screening, a confirmation assay was conducted to determine whether potentially positive samples for T-DM1 antibodies that were detected by the initial screening assay were true or false positives. A total of three samples were identified as true positives, which showed signal inhibition values above the specificity cutoff, and all of them were at 360 h after injection. C.Current biotherapeutics are designed to be capable of multiple functions by increasingly complex structures. Since T-DM1 has the characteristics of small-molecule drugs and antibodies, there are unique challenges in developing bioanalytical methods for T-DM1 evaluation compared to developing methods for the evaluation of conventional therapeutic antibodies or small-molecule drugs. Since the small-molecule drug and the antibody of T-DM1 are critical to its activity, assays suited to quantitating these components are required . Anothermax were similar, but the Cmax of trastuzumab was approximately 1.2-fold higher than that of T-DM1. These results were consistent with the appearance of free DM1 due to deconjugation from T-DM1. The Cmax of T-DM1 in another rat study was lower than that of our study. The difference in these results might be due to the different sampling times between the studies. The first sampling point was 10 h, which was an insufficiently earlier time point to be considered an early phase sampling for PK [During preclinical development, the characterization of an ADC’s PK parameters is very important to predict its effects in humans. After administration, circulating levels of total trastuzumab and conjugated trastuzumab are expected to decrease over time. Our data established exposure–response relationships by evaluating PK parameters in rats. As expected, the total trastuzumab and conjugated trastuzumab concentrations at Cg for PK . In a prg for PK . The cirg for PK . Althougg for PK , the cleg for PK ,44. The g for PK . Althougg for PK . Similarg for PK ,32 and ag for PK . This evADCs can cause an ADA response like other biological drugs. It is important to monitor and evaluate ADA responses to ADCs during both clinical and preclinical studies to understand the PK, safety, and efficacy over time . We alsoIn conclusion, the results in this study suggested that the overall PK profile and immunogenicity translated well from rats to monkeys to humans. The bioanalytical methods optimized in this study provided a valuable approach to help understand the safety and efficacy of T-DM1. It will be important to continue using a variety of existing and new bioanalytical methods that provide appropriate information to help understand the safety and efficacy of various ADCs in preclinical and clinical studies. The data presented in this study establishes a systematic bioanalysis of ADCs with validated assays including drug stability in a matrix. The optimized ADA assays also improved the precise pharmacokinetic interpretation from quantification with a systematic bioanalysis process of ADCs. In addition, our bioanalytical experiences may support the development of bioanalytical methods on a case-by-case basis, using ADC characteristics to facilitate the future development of ADCs.


In this work, we engineered a corn-straw-based bio-foam material under the inspiration of the intrinsic morphology of the corn stem. The explosion pretreatment was applied to obtain a fibrillated cellulose starting material rich in lignin. The in situ esterification of cellulose was adopted to improve the cross-linking network of the as-developed foam bio-material. The esterification of lignin was observed in the same procedure, which provides a better cross-linking interaction. The esterified corn-straw-derived bio-foam material showed excellent elastic resilience performance with an elastic recovery ratio of 83% and an elastic modulus of 20 kPa. Meanwhile, with surface modification by hexachlorocyclotriphosphazene-functionalized lignin as the flame retardant (Lig-HCCP), the as-obtained bio-foam material demonstrated quite a good flame retardancy (with 27.3% of the LOI), as well as a heat insulation property. The corn-straw-derived bio-foam material is prospected to be a potential substitution packaging material for widely used petroleum-derived products. This work provides a new value-added application of the abundant agricultural straw biomass resources. Porous polymer materials have applications in extensive aspects, such as purification, separation, drug or fertilizer delivery, and packaging material, etc. In consideration of only packaging materials, there is a huge demand for lightweight plastics, such as polyethylene (PE) and polypropylene (PP), as well as synthetic polymer foams, such as polyurethane (PU) and polystyrene (PS), at present and a continuous increasing trend in the near future with changes in lifestyle and the increasing transportation of commodities. It is estimated that about 265 million tons of synthetic plastic are produced each year, while only 0.7 million tons of biodegradable plastic are made annually . As a reConsidering the preparation techniques for porous organic polymer scaffolds, supercritical carbon dioxide foaming ,24, hardLignin has considerable potential in the development of sustainable flame retardants for polymers due to its aromatic skeleton and high char-forming capability after combustion ,32,33. HThe present work investigates the feasible engineering of agricultural straw into a foam material as a potential sustainable alternative to non-biodegradable petroleum-based products, for example, packaging applications for shipping convenience and safety. Under the inspiration of the ordered porous architecture of the inner part of the corn stem, which presents a certain compression and flexural resilience, we adopt corn straw as the raw material to prepare a bio-foam material using a dissolution–regeneration method together with freeze drying. Lignin was modified with HCCP and introduced into the as-prepared bio-foam material as a flame retardant.Cotton pulp cellulose was purchased from Xinxiang Chemical Fiber Co., Ltd. , and dealkaline lignin and chloroform were purchased from Shanghai Macklin Biochemical Co., Ltd. The vinyl acetate (VA), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), carboxymethylcellulose sodium (CMCNa), calcium disodium edetate (EDTACa), hexachlorocyclotriphosphazene (HCCP), and sodium hydroxide (NaOH) were purchased from Chengdu Kelong Chemical Reagent Factory. The tetrabutylammonium hydroxide aqueous solution  was obtained from Zhenjiang Runjing High Purity Chemical Co., Ltd. , which was condensed to 50 wt% with a rotary evaporator (40 °C) before use.The corn straw was collected from the suburb of Chengdu, Sichuan. The corn straw was detected to contain 49.7 wt% cellulose, 29.8 wt% hemicelluloses, 11.6 wt% lignin, 7.1 wt% lipids, and 1.8 wt% ash. It was steam exploded with a self-made machine under the conditions of 2.2 MPa and 30 min of steaming time. After boiling and washing with deionized (DI) water, the product was dried to obtain the steam-exploded corn straw (SEC). The SEC was tested to contain 63.5 wt% cellulose, 2.3 wt% hemicelluloses, 15.6 wt% lignin, 13.9 wt% lipids, and 4.7 wt% ash. A cellulose analyzer  was used to analyze the main components of the raw corn straw and SEC according to the Van Soest method.−x according to the esterification efficiency (x: the number represents the degree of substitution).As included in the −x were added into a reaction bottle and mixed under magnetic stirring at 60 °C. The cross-linking agents, which consist of 0.0216 g of CMCNa and 0.0144 g of EDTA in 1.2 g of water, were then added. The mixture was poured into a cylinder mold of 1.5 cm × 2 cm (diameter × height). After standing overnight, solvent exchange was conducted to obtain a wet gel using ethanol. Finally, the samples were dried by a freeze dryer at −50 °C under the pressure of 18 Pa for 48 h, and the bio-foams were obtained. Meanwhile, the bio-foams prepared from SEC and ECS−x were respectively named as SEC foam and ECS−x foam.The preparation of the bio-foams from steam-exploded corn straw was according to a common procedure as follows: 2 g of TBAH (50 wt%), 8 g of DMSO, and 0.2 g of SEC or ECSThe flame retardant was synthesized as detailed in the following procedure. Dealkali lignin (0.5 g) was dispersed in DMF (15 mL) to be fully dissolved and then pyridine (2 g) was added. By adding a solution of HCCP (1.5 g) in 5 mL DMF, the mixture was allowed to stir at 80 °C for 8 h. Finally, the product was separated by centrifugation at 8000 rpm for 10 min, followed by washing with alcohol and DI water. The purified product was obtained after freeze drying at −50 °C under the pressure of 18 Pa for 48 h, and the resultant product was named Lig-HCCP.−4.5 solution (the solvent was TBAH: DMSO with a mass ratio of 2:8), the cross-linking agents EDTA and CMC were added. Then, ECS−4.5 was fully dissolved in the flame retardant Lig-HCCP (the mass ratio of Lig-HCCP to straw acetate was 2:8). Finally, the resulting mixture was poured into a mold, regenerated, dialyzed, and then freeze dried to obtain the bio-foam, which was labeled the Lig-HCCP-ECS−4.5 foam.The preparation of the flame-retardant corn-straw-derived bio-foam material was conducted in a common process as follows. After preparing 2 wt% ECS–1, with 32 scans over the range from 4000 to 400 cm–1.A Fourier-transform infrared spectrometer  was used to analyze the chemical structure of the specimens under various conditions. FTIR spectra were collected at a spectral resolution of 4 cm002 is the maximum intensity at 22.5°, and Iam is the lowest intensity of the amorphous area at 18.7°.The aggregate structures of the samples were detected on an X-ray diffractometer . The test adopted a copper target, and the receiving slit was 0.3 mm, the operating voltage was 40 kV, the current was 30 mA, the scanning speed was 10°/min, and the scanning range was set from 5 to 60°. The crystallinity index (CrI) was calculated by Segal’s equation :(1)CrI=I13C NMR spectra of esterified cellulose and lignin were collected with a Bruker Advance III 400 MHz spectrometer at room temperature with 1940 scans and a receiver gain of 1150 (the result is shown in Solid-state cross-polarization/magic-angle spinning (CP/MAS) Scanning electron microscopy  was used to observe the microstructure of the materials. The samples were brittle broken and fixed on the copper sample stage. After spraying gold with the ion sputtering instrument , the samples were detected under a voltage of 12 kV.The thermal properties of the samples were performed by DSC . The temperature ranged from −10 °C to 280 °C and the heating rate was 10 °C/min in a nitrogen atmosphere. The thermal stability was also tested by a thermal gravimetric analyzer  with a heating rate of 10 °C/min; the temperature ranged from 0 °C to 800 °C in a nitrogen atmosphere.The compressive properties of the bio-foams were tested by an electronic universal testing machine  at room temperature at a rate of 5 mm/min.e and Vc respectively represent the volumes (mL) of HCl solution added to the esterified straw and straw (control). The m indicates the molar mass of the attached acetyl residue [A chemical reaction method was adopted to test the esterification efficiency, which was the degree of substitution of -OH. Amounts of 0.2 g of ECS and 10 mL of aqueous ethanol (70 vt%) were mixed and stirred for 30 min. Then, 5 mL of NaOH solution (0.5 N) was also added and the mixture was stirred for 48 h at 60 °C. At last, the superfluous NaOH was neutralized with 0.1 N HCl: residue .−4.5 foam at 60 °C and 100 °C. The simulation parameters were obtained according to the above tests. The parameters were shown in the following The thermal conductivity of the bio-foams was tested by a thermal constant analyzer  at room temperature. The molar heat capacity at constant pressure was tested by DSC . The true density of the bio-foams was measured by ULTRAPYC1200e  to calculate the porosity using the method of inert gas replacement (helium) at 100 °C. COMSOL software was used to simulate the thermal insulation performance of Lig-HCCP-SECsThe limiting oxygen index (LOI) is the lowest volume fraction concentration of oxygen in a mixture of oxygen and nitrogen when the polymers start to burn at room temperature. It was measured at room temperature by a TTech-GBT2406-1 intelligent critical oxygen index analyzer according to GB/T 2406.2-2009 standard with specimen dimensions of 100 mm × 10 mm × 10 mm.The macroscopic and microscopic morphology of the raw corn straw in a vertical section and a cross section are shown in In the raw corn straw, cellulose is tightly packed with hemicellulose and lignin to form a rigid cell wall structure, which severely prevents esterification ,41,42. I−4.5, which was prepared under the optimum condition, was determined. Under a significant level of 0.05, the dosage of VA showed a significant difference.In order to clarify the impact factors on the esterification efficiency, an orthogonal experiment with three factors and four levels was designed  were almost the same, 23.5% and 23.7%, accordingly. After modification with the flame retardant (Lig-HCCP), the LOI of the Lig-HCCP-ECS−4.5 was improved to 27.2%, which was due to the flame retardant material. Combined with the previous analysis, it could be inferred that the existence of N and P in the Lig-HCCP-ECS−4.5 foam could be decomposed during combustion and released gas that inhibited the combustion [The limiting oxygen index (LOI) of the bio-foam materials before and after modification with the Lig-HCCP were detected. It was found that the LOI values of the steam-exploded corn straw (SEC)-derived bio-foam and the esterified steam-exploded corn straw (ECSmbustion . At the −4.5 bio-foam had a compressive strength of 7.9 kPa, it showed an elastic recovery ratio of 83% and an elastic modulus of 20 kPa. The as-prepared bio-foam materials also presented quite good heat insulation and flame retardance. In the future, this corn-straw-based bio-foam material could be potentially used in the production of packaging materials, thus creating alternatives for petroleum-based synthetic polymers, for example, polyurethane foam.In summary, corn straw was adopted as the starting material to obtain bio-foam materials with a facile dissolution–regeneration method in this work. The steam-explosion pretreatment of the pristine corn straw was conducted to obtain the fibrillated cellulose reach in lignin, which was then esterified in situ to improve the cross-linking reaction efficiency. Furthermore, the as-prepared bio-foam materials were modified with the lignin-derived flame retardant Lig-HCCP. The results show that this esterification method can successfully modify the hydroxyl groups in both cellulose and lignin, which can efficiently improve the interaction between lignin and cellulose to result in the formation of a cross-linking network. The SEC bio-foam had a maximum compression strength of 18.3 kPa at 40% stress. Although the ECS


Patients with cardiomyopathies and channelopathies are usually younger and have a predominantly arrhythmia-related prognosis; they have nearly normal life expectancy thanks to the protection against sudden cardiac death provided by the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) is an effective alternative to the transvenous ICD and has evolved over the years. This study aimed to evaluate the rate of inappropriate shocks (IS), appropriate therapies, and device-related complications in patients with cardiomyopathies and channelopathies who underwent modern S-ICD implantation.P = 0.032). No significant differences were noted over a median follow-up of 43 months . The rate of appropriate shocks at 12 months was 2.3% (95% CI: 1.1–4.1) in patients with cardiomyopathies and 2.1% (95% CI: 0.6–5.3) in patients with channelopathies (P = 1.0). The rate of device-related complications was 0.9% (95% CI: 0.3–2.3) and 3.2% (95% CI: 1.2–6.8), respectively (P = 0.074). No significant differences were noted over the entire follow-up. The need for pacing was low, occurring in 0.8% of patients.We enrolled consecutive patients with cardiomyopathies and channelopathies who had undergone implantation of a modern S-ICD from January 2016 to December 2020 and who were followed up until December 2022. A total of 1338 S-ICD implantations were performed within the observation period. Of these patients, 628 had cardiomyopathies or channelopathies. The rate of IS at 12 months was 4.6% [95% confidence interval (CI): 2.8–6.9] in patients with cardiomyopathies and 1.1% (95% CI: 0.1–3.8) in patients with channelopathies (Modern S-ICDs may be a valuable alternative to transvenous ICDs in patients with cardiomyopathies and channelopathies. Our findings suggest that modern S-ICD therapy carries a low rate of IS.http://clinicaltrials.gov/Identifier: NCT02275637.URL:   The rate of inappropriate shocks at 12 months is higher in patients with cardiomyopathies than in those with channelopathies (4.6% vs. 1.1%), despite similar values over the long-term follow-up.Device-related complications at 12 months are reported in 0.9% of patients with cardiomyopathies and 3.2% of those with channelopathies. The management of all device-related complications requiring surgical intervention is safe and effective.Over a long-term follow-up, the need for pacing is low, occurring in 0.8% of the overall population.1–10 Patients with cardiomyopathies and channelopathies are usually younger and have a predominantly arrhythmia-related prognosis; they may therefore survive for many decades and have nearly normal life expectancy thanks to the protection against SCD provided by the ICD.1–10 However, the improvement of survival due to ICD therapy is associated with a significant rate of inappropriate shocks (IS) and lead-related complications, which are higher than in the general ICD population.11 The subcutaneous ICD (S-ICD) is now recognized to be an effective alternative to the transvenous ICD (TV-ICD) for the prevention of SCD among high-risk patients who do not need pacing or cardiac resynchronization therapy.12–14 Indeed, the S-ICD, in addition to displaying the same efficacy in interrupting life-threatening VA, enables the risk of systemic infection and lead failure to be reduced, which are the most common complications of TV-ICD and often require surgical revision.14 Early studies on the S-ICD demonstrated the effectiveness of the first-generation devices, despite relatively high IS rates. However, S-ICD therapy has evolved over the years, and more recent data show that the use of high-rate cut-off, current-generation electrogram filtering and discrimination algorithms have significantly reduced IS rates;15–19 with modern devices, the reported rate is 2.4%/year, a figure even lower than that of TV-ICD with modern programming.13 However, few studies have been conducted on the performance of S-ICD in patients with cardiomyopathies and channelopathies.20–26 Because of predisposing electrocardiogram (ECG) depolarization/repolarization changes, these patients have a potentially increased risk of double QRS counting or P- and/or T-wave oversensing (TWO), potentially inducing IS delivery. Long-term data on modern S-ICD and the type of implantation technique in patients with cardiomyopathies and channelopathies are lacking. Thus, the aim of this multicentre study was to evaluate the rate of IS, appropriate therapies, and device-related complications during long-term follow-up in patients with cardiomyopathies and channelopathies who undergo modern S-ICD implantation.Life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD) may be related to cardiomyopathies and channelopathies. In patients with cardiomyopathies and channelopathies who are at risk of SCD, the implantable cardioverter defibrillator (ICD) provides the most effective life-saving therapy.de novo implantation of a modern S-ICD , at 66 Italian centres (see Appendix) from January 2016 to December 2020, and who were followed up until December 2022. For the aim of this analysis, we excluded old-generation pulse generators , which were not equipped with the SMART Pass filter, and patients with a follow-up period shorter than 2 years. Cardiomyopathies and channelopathies were defined as either structured cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM), or channelopathies including Brugada syndrome (BrS), long-QT syndrome (LQTS), and idiopathic ventricular fibrillation (IVF). Cardiomyopathies and channelopathies were diagnosed according to general guidelines and/or available task force consensus statements.27–29 Baseline clinical characteristics, electrocardiographic data, indication for implantation, ECG screening, and device parameters were collected. The registry was ethically approved by the host institutions and was conducted according to the Helsinki declaration. All patients provided written informed consent for data storage and analysis.The present study was a retrospective analysis of data collected within the framework of the prospective ‘Rhythm Detect’ registry. The study population consisted of consecutive patients with cardiomyopathies and channelopathies who had undergone 30 Antibiotic prophylaxis was administered 1 h before the procedure. All S-ICD implantations were performed by experienced operators. According to physician preference, the pulse generator was positioned in a subcutaneous pocket or in an intermuscular position (between the serratus anterior and the latissimus dorsi muscles) as previously reported in detail.32 For lead deployment, physicians adopted the three-incision technique, i.e. pocket incision, xiphoid incision, and superior incision at the sternomanubrial junction, or the two-incision technique, i.e. the superior incision is avoided by positioning the lead by means of a peel-away sheath introducer.32 The position of the lead and pulse generator relative to the heart silhouette was checked by means of fluoroscopy. At the end of the procedure, the decision to perform defibrillation testing (DT) was left to the discretion of the implanting physician. Defibrillation testing was considered successful if the device detected and terminated the induced ventricular fibrillation (VF) by using ≤ 65 J shock energy. Programming of the parameters for the detection of ventricular tachycardia (VT) or VF was also left to the discretion of the implanting centre. Physicians were free to set parameters on hospital discharge and adjust them during follow-up, in order to fit the specific characteristics of the patient, and on the basis of the best available evidence. The sensing vector  was automatically selected by the device at the time of implantation and optimized during supine and upright positions before discharge. After implantation, patients were followed up in accordance with the standard practice of the participating centres.Before implantation, all patients were screened for eligibility for S-ICD by means of the Boston Scientific screening tool, which is based on the surface ECG limb lead recording over the left and/or right parasternal regions to simulate the three S-ICD sensing vectors. To be eligible for S-ICD implantation, at least one vector had to pass the test in both the erect and supine postures. Implantation was performed in an electrophysiology laboratory under standard sterile conditions and general anaesthesia, local anaesthesia with conscious sedation, or ultrasound-guided serratus anterior plane block, as previously reported.The primary endpoint of the study was the rate of IS. An S-ICD shock was classified as inappropriate when it was delivered for any rhythm other than VF or VT, including supraventricular arrhythmias, cardiac/non-cardiac oversensing, or device or lead malfunction. Secondary endpoints consisted of appropriate shocks and device-related complication rates. For the analysis of therapy efficacy, we reported when the first shock successfully converted the VA to sinus rhythm and the final efficacy. Complications were defined as events that led to intervention or prolongation of hospitalization and included device infection, lead repositioning or replacement, and other complications related to the lead or generator. The rates of endpoints were evaluated at 12 months, and cumulative survival rates were also measured over the entire follow-up period.P value <0.05 was considered significant for all tests. All statistical analyses were performed by means of R: a language and environment for statistical computing .Descriptive statistics are reported as means ± SD for normally distributed continuous variables or medians and interquartile range (25th–75th percentile) in the case of skewed distribution. Normality of distribution was tested by means of the non-parametric Kolmogorov–Smirnov test. Categorical variables are reported as percentages. Differences were compared by means of Mann–Whitney or Wilcoxon non-parametric tests for non-Gaussian variables. Differences in proportions were compared by means of a Chi-square analysis. Analysis of the cumulative survival rates was made by means of the Kaplan–Meier method, and the distributions of the groups were compared by means of a log-rank test. A de novo S-ICD implantations were performed within the observation period. Of these patients, 628 had cardiomyopathies or channelopathies: dilated cardiomyopathy , HCM , ACM , BrS , LQTS , and IVF . Table 1 shows the baseline clinical characteristics and implantation variables of the overall study population and of patients stratified by disease. The S-ICD generator was positioned in a standard subcutaneous pocket in 144 (23%) patients and in an intermuscular pocket in 484 (77%); the two-incision technique was adopted in 581 (93%) procedures. On pre-discharge programming, the median conditional zone cut-off rate was 210 b.p.m. (25th–75th percentile: 200–220) and the shock zone cut-off was 230 b.p.m. (25th–75th percentile: 210–250). No major differences in device programming were found among groups (Table 1). Cardioversion at a shock energy of ≤ 65 J was tested in 490 (78%) patients. In patients who underwent DT, success at a shock energy of ≤ 65 J was reported in 475 (97%) cases. In one patient with BrS, successful cardioversion was not obtained with an 80 J shock and the S-ICD was not implanted.A total of 1338 consecutive P = 0.032). The IS rates at 12 months according to the type of disease are shown in Table 2. Figure 1 shows the Kaplan–Meier analysis of time to first IS, stratified by cardiomyopathy vs. channelopathy and different types of diseases. No significant differences were noted over the entire follow-up period . The causes of IS and the distribution among different diseases are reported in Figure 2. The most common reason for IS was non-cardiac oversensing both in the overall study population  and in all subgroups. The source of non-cardiac oversensing was myopotentials in 9 (1.4%) patients and other sources in 17 (2.7%) patients. Of the nine cases of oversensing of myopotentials, four were reported during sports activity (gym training in three cases and skiing in one case), the others during daily activities. Overall, the vast majority of IS  was managed without requiring S-ICD surgical revision; 36 were solved by means of S-ICD reprogramming. In the remaining 16 cases, no reprogramming or other actions were performed; only drug therapy adjustments were reported in some cases. After the first IS, 25 out of 63 patients experienced additional episodes. The time-course of all IS (first occurrence and recurrences) reported during the observation period in patients with cardiomyopathies and channelopathies is shown in Figure S1.In the overall study population, over a median follow-up of 43 months (25th–75th percentile: 28–57), 21 (3%) deaths occurred. Inappropriate shocks were reported in 63 (10%) patients: 47 (11%) with cardiomyopathies and 16 (8%) with channelopathies. Specifically, IS were recorded in 23 (12%) patients with dilated cardiomyopathy, 15 (8%) with HCM, 9 (14%) with ACM, 6 (6%) with BrS, 3 (19%) with LQTS, and 7 (10%) with IVF. The rate of IS at 12 months was 3.5% [95% confidence interval (CI): 2.2–5.3] in the overall study population. The rate at 12 months was 4.6% (95% CI: 2.8–6.9) in patients with cardiomyopathies and 1.1% (95% CI: 0.1–3.8) in patients with channelopathies . Kaplan–Meier analysis of time to first device-related complication is shown in Figure 4 . The details of the events that occurred and their management are reported in Table 3. No sequelae were reported. The most common device-related complication was premature battery depletion requiring device replacement, which occurred in 50 (8%) patients. The need for cardiac resynchronization pacing or anti-bradycardia pacing was reported in five (0.8%) patients and required device explantation in four patients (see Table 3 for details). No device explantation because of the need for anti-tachycardia pacing (ATP) was noted.Appropriate shocks were delivered in 38 (6%) patients during follow-up. The first shock was effective in 34 (90%) patients, and the final conversion rate was 97% (37 out of 38). Seventy-nine device-related complications were reported in 78 (12%) patients during follow-up. In the overall population, the rate of appropriate shocks and device-related complications at 12 months was 2.2% (95% CI: 1.2–3.7) and 1.8% (95% CI: 0.9–3.1), respectively. The rates of appropriate shock and device-related complications at 12 months according to the type of disease are reported in In this multicentre study, we evaluated the rate of IS and device-related complications during long-term follow-up in patients with cardiomyopathies and channelopathies who had undergone S-ICD implantation. The main findings are:1.Over a median follow-up of 43 months, IS occurred in 10% (3.5% at 12 months) of patients who received a modern device, with SMART Pass filter activated in most cases and high detection cut-off rates programmed. Non-cardiac oversensing was the leading cause of IS, suggesting the potentially positive effect of modern S-ICD in reducing IS due to TWOS.2.The rate of IS at 12 months was higher in patients with cardiomyopathies than in those with channelopathies (4.6% vs. 1.1%), despite similar values over the entire follow-up period.3.Patients with ACM presented the highest rate of IS at 12 months (10.9%).4.Device-related complications were reported in 12% of patients (1.8% at 12 months). Pocket and lead complications were few , while premature battery depletion was the most common (8%) complication. The management of all device-related complications requiring surgical intervention was safe and effective.5.S-ICD was effective in terminating clinical VA, and we did not report a need for S-ICD explantation and TV-ICD reimplantation to ensure ATP therapy.6.The need for anti-bradycardia pacing was low, occurring in 0.8% of patients.1–10 The common denominators of patients with cardiomyopathies and channelopathies are younger age than the typical ICD population with coronary artery disease referred for primary or secondary prevention of SCD, no or minor comorbidities, and an active lifestyle.1–11 Young patients with cardiomyopathies and channelopathies have a predominantly arrhythmia-related prognosis and may survive for many decades and have nearly normal life expectancy thanks to the protection against SCD provided by the ICD,1–11 as confirmed by the low mortality rate observed in our study group (3% over a median follow-up of 43 months). In these patients, IS are frequently caused by either supraventricular tachycardia or abnormal sensing  and have the potential to reduce the patient’s quality of life and compromise the acceptance of ICD therapy. Accordingly, the risk/benefit ratio should be carefully assessed when considering ICD implantation for primary prevention, especially in patients with cardiomyopathies and channelopathies, and a high priority should be given to preventing IS by means of adequate device selection, targeted device programming, and modern discriminating software.33–35 In a large meta-analysis by Nordkamp et al.,10 which comprised 4916 young TV-ICD patients with inherited arrhythmia diseases (IADs), the crude annual IS rate was 4.7% per year. More recently, device manufacturers have implemented technological improvements in order to reduce inappropriate ICD interventions; this has resulted in more effective models of device programming and improved arrhythmia detection algorithms.15–19 Indeed, a systematic review and meta-analysis reported an annual IS rate of 6.4%, which later progressively decreased over time and significantly dropped to 1.9% in one of the more recent studies.34 Recently, Auricchio et al.36 conducted a subanalysis of the PainFree SST Study in which they specifically assessed the rate of IS in patients with IADs who had received TV-ICD endowed with the SmartShock Technology. The authors found that, in patients with IAD, the annualized IS rate was 1.6%. The study had some limitations, i.e. the small sample; the incomplete spectrum of IADs in analysis, which did not include important diseases such as HCM, dilated cardiomyopathy, catecholaminergic polymorphic VT, and short-QT syndrome; and the use of a TV-ICD from a single manufacturer. However, it confirmed the continuous improvement of detection algorithms, which may have a major impact on the patient’s quality of life, especially that of young IAD patients, who will have ICDs for a much longer time.Patients with cardiomyopathies and channelopathies constitute a heterogeneous group of patients at increased risk of SCD.17–19 However, data on the performance of the S-ICD in patients with cardiomyopathies and channelopathies are scant, excluding observations on specific patient groups.20–26 Moreover, there are concerns regarding the presence of ECG depolarization/repolarization abnormalities, which may trigger IS, and the inability to deliver ATP, which may be an effective ‘pain-free’ therapy.The most common complication of the TV-ICD is long-term transvenous lead issues; the S-ICD avoids such problems. Observational studies have shown the overall efficacy and safety of the S-ICD over medium- and long-term follow-up, despite relatively high IS rates. However, S-ICD therapy has evolved over the years, and more recent data show that the use of high-rate cut-offs, modern S-ICD with modern electrogram filtering, and discrimination algorithms has significantly reduced IS rates; indeed, with modern devices, the reported rate is 2.4%/year, a figure even lower than that of TV-ICD with modern programming.22 which involved patients with various IADs  who had received an S-ICD, the IS rate was 3.2% over a median follow-up of 31.0 ± 14.2 months. In the Effortless study cohort of S-ICD patients with channelopathies, the incidence of IS was 8.5% over 3.2 years of follow-up and the annualized IS rate was lower among S-ICD patients than TV-ICD patients (2.7%/year vs. 3.8%year).20 In that study, most IS were caused by oversensing, principally cardiac oversensing (5.0%), including TWOS. In our patients with channelopathies, the IS rate was lower (1.1% at 12 months) than in the Effortless study,20 suggesting the potentially positive effect of the new-generation S-ICD in reducing IS due to TWOS.In a previous study by Rudic et al.,21 assessed the long-term outcome of S-ICD patients in comparison with TV-ICD patients in a cohort of patients with IADs; a relatively low incidence of IS (1.9%/year) was observed, and no statistically significant differences emerged between S-ICD and TV-ICD patients (though the rate was lower in the S-ICD group: 1.4%/year vs. 2.5%/year). These findings may be explained by the fact that modern devices were used in most S-ICD patients and improved programming strategies in both types of devices. The relatively higher rate of IS in our study may be explained by the difference between the study populations, in that ours had a higher prevalence of dilated cardiomyopathies, HCM, and, especially, ACM which is historically associated with higher rates of IS.37 Indeed, our patients with ACM had the highest rate of IS.A more recent study by Kuschyk et al.34 found that studies with longer mean follow-up had lower annualized IS rates. It is likely that some patients are at higher risk of IS than others and tend to experience events earlier, leaving a lower risk group to the later follow-up times. In order to allow comparisons between groups, we estimated the IS rate at 12 months and observed a higher rate in patients with cardiomyopathies. This difference was not confirmed over the entire follow-up period, probably for the same reason. Indeed, patients with channelopathies might manifest IS later, owing to the evolution of the ECG signal detected by the device.In their meta-analysis, Auricchio and co-workers18Regarding the causes of IS, non-cardiac oversensing was the leading cause in our population. This can certainly be explained by the SMART Pass filter of modern S-ICD, which attenuates cardiac oversensing and especially TWOS.19 The number of patients who experienced IS recurrences did not appear to be high in both groups. In particular, both first therapies and recurrences seemed infrequent in patients with channelopathies after the second year.Most IS in the present study were successfully managed by reprogramming the device, without system revision, confirming previous findings.12 Early battery depletion was the most frequent cause of system revision in our study. Indeed, in 2020, the EMBLEM S-ICD was subjected to a safety notification because of an increased risk of rapid battery depletion (Boston Scientific urgent field action REF.92400926-FA). In addition, 4.8% of the devices underwent normal battery depletion, being replaced after about 6–7 years, depending on the number of therapies delivered and in line with the generator projected longevity. The rates of pocket and lead complications were low. This can be ascribed to the fact that the pulse generator was most often implanted in the intermuscular space rather than in the traditional subcutaneous pocket and the two-incision technique was used for lead deployment.32 Indeed, these approaches have recently been shown to result in fewer device-related complications and composite endpoints of complication or IS over medium-term follow-up.32Overall, device-related complications that required revision were relatively infrequent, i.e. 12% over a median follow-up of 43 months (1.8% at 12 months), and were comparable among the different types of diseases. In comparison, the rate of device-related complications at 1 year was ∼4% among the S-ICDs in the PRAETORIAN study.23 we observed a relatively low rate of appropriate shocks in S-ICD patients with cardiomyopathy and channelopathies. The high-rate cut-off programmed in S-ICDs and the multistep discriminative sensing algorithm may have reduced therapies, thus allowing many VA to self-terminate while still protecting against life-threatening VT/VF. Indeed, in previous studies, appropriate ICD intervention rates were lower in the S-ICD group than in the TV-ICD group, with no reduction in overall efficacy.38Like other investigators,21 This may be explained by the fact that the majority of appropriate shocks in patients with cardiomyopathies and channelopathies is triggered by fast or polymorphic VT, which are less amenable to ATP.21 Thus, the decision of whether to implant an S-ICD in patients with structural cardiomyopathies needs to be patient-specific; indeed, the probability of lead-related complications, which are typically observed in TV-ICD patients, must be balanced with the likelihood of recurrent VT, which may be effectively pace-terminated.The main potential limitation of the S-ICD is its inability to deliver ATP, which may be an effective ‘pain-free’ therapy in patients with structural heart diseases. In our study, no patients had the device removed because of a perceived need for ATP. Indeed, in TV-ICD patients with cardiomyopathies and channelopathies, the availability of ATP therapy is not reported to result in fewer appropriate shocks.39 (iii) tracking the sensed R-wave amplitude in various vectors at rest, during effort or Ajmaline challenge in BrS patients;41 (iv) considering patients with at least two suitable vectors, as the potential decline in R-wave amplitude during follow-up, especially in ACM patients, increases the risk of cardiac and/or non-cardiac oversensing;39 and (v) performing provocative tests at follow-up visit aiming for myopotential inducibility to select the optimal sensing vector.42Possible strategies that could further reduce IS in patients with channelopathies and cardiomyopathies who receive modern S-ICDs are (i) thorough pre-implantation ECG screening and device programming with a high-rate cut-off (shock zone >250); (ii) targeting a surface ECG R-wave amplitude >1 mV and an appropriately high R/T and R/P amplitude ratio on implantation, which may allow better discrimination;The limitations of our study should be acknowledged. First, its observational and retrospective design may have introduced an inherent bias. Second, the small size of some groups did not allow us to accurately estimate the rate of endpoints or make direct comparison between groups. No direct comparison was made between TV-ICD and S-ICD nor between the traditional technique of S-ICD implantation and the intermuscular two-incision technique; however, this goes beyond the aim of the present study. Clearly, large randomized studies involving a predefined comparable cohort of patients with new-generation TV-ICDs endowed with updated discrimination algorithms and software would be needed in order to accurately define the clinical benefit or harm resulting from device choice. Despite our long follow-up, a relatively small number of events occurred, and this might have prevented us from identifying predictors. Finally, as all our procedures were performed by experienced operators, the results may not be widely applicable in less experienced centres. Despite these limitations, the data presented are unique in several ways and make an important contribution to the scant published data regarding the clinical performance of modern S-ICDs in patients with channelopathies and cardiomyopathies.According to our findings, modern S-ICDs may be a valuable alternative to TV-ICDs in patients with cardiomyopathies and channelopathies who do not need anti-bradycardia pacing or ATP therapy. However, the potential risk of IS, mainly due to non-cardiac oversensing, should be considered. Our findings suggest the potential positive effect of modern S-ICD in reducing IS due to TWOS. Strategies for avoiding IS must be adopted.euad239_Supplementary_DataClick here for additional data file.